Responsive to HL-133, our long-term goal is to improve pain control in adults with sickle cell disease (SCD) by phenotypic characterization of their chronic pain experiences. Often the etiology of SCD pain is thought to be only episodic, driven by mechanisms of somatic or visceral tissue damage, but it has become increasingly clear that adults with SCD also experience chronic pain. The lack of sufficient normative data for quantitative sensory testing (QST) measures in adults of African descent, however, is a barrier that must be addressed simultaneously with fundamental work to characterize chronic SCD pain phenotypes across time. We propose to determine normative QST values in 100 healthy African Americans to provide comparative data for an 18- month longitudinal study with repeated measures across seasons among 180 adult outpatients with SCD pain. We will characterize sensitization via quantitative sensory testing (QST) measures at three sites (2 painful, 1 non-painful) in adults with SCD pain; 4 times all 6 months apart. All subjects will complete well- validated, state-of- the-science self-report tools to characterize the perceived pain and its impac on quality of life and contribute samples for genetic and epigenetic analyses. Measures include: (1) mechanical QST (von Frey filaments), (2) thermal QST (cool/warm sensations, heat/cold pain thresholds), (3) self-report pain (PROMIS, PAINReportIt); (4) self-report neuropathic pain (S-LANSS, NPSI); (5) self-report quality of life (ASCQ-ME); and (6) genetic and epigenetic data (polymorphisms in the monoamine neurotransmitter systems, microRNA, and a global epigenetic marker LINE-1). Specific aims are: Aim 1. Based on normative values from 100 African American healthy volunteers, to compare the prevalence of pain sensitization in the healthy volunteers and 180 adults with SCD using mechanical and thermal stimulation of sensory fibers (A [mechanical, von Frey QST], A-delta [cold QST], C [heat QST]). Hypothesis (HO): A significantly higher proportion of the SCD sample will report allodynia/hyperalgesia than healthy volunteers. Aim 2. From the 180 adults with SCD, to discover the chronic pain phenotype groups represented by the variability in the type of sensitization (none, central, peripheral, mixed) and pain characteristics (POMIS, PAINReportIt, S-LANSS, NPSI) and determine differences in self-report pain by the pain phenotypes. HO: Pain phenotypes will differ significantly on self-report pain (e.g., intensity, sensory, affective, pattern scores). Aim 3. Determine the genetic and epigenetic markers, pain treatment, environmental factors (season, temperature, wind), and quality of life scores associated with each phenotype across time among 180 adults with SCD. HO: Pain phenotypes with central or mixed sensitization will be associated with epigenetic markers (increased LINE-1 methylation, circulating let-7 microRNAs) and gene polymorphisms at the monoamine neurotransmitter network, high opioid doses, cold-related factors, and poorer quality of life. Findings will guide studies of adults to discover pain therapies for different pain phenotypes that effectively control chronic SCD pain and improve quality of life.